1. Field of the Invention
The present invention relates to gelified microspheres, to their method of preparation and to their applications.
2. Discussion of the Background
Microspheres, which are particles of spherical shape, the size of which ranges, generally, between 1 and 1250 .mu.m, are composed of a support material containing the encapsulated substance and are of particular advantage, either when it is desirable to administer a medicament in a form which makes possible the controlled release of the active component over a certain period, in order to provide for a prolonged pharmacological effect, or when it is necessary to protect the said active component from premature degradation in the digestive tract.
Depending on the structure of the support material, two types of microcapsules are distinguished:
microcapsules of reservoir type, in which the support material is a solid envelope of variable thickness containing the substance to be encapsulated, PA1 microcapsules of matrix type, also known as microspheres, in which the support material is a continuous network in which the substance to be encapsulated is dispersed. PA1 the phase-separation method, described in particular in U.S. Pat. No. 4,675,189 and Application EP 52,510, which describes microcapsules prepared by a phase-separation technique using a coacervation agent, such as mineral oils or vegetable oils. PA1 the solvent-evaporation method, described in particular in U.S. Pat. No. 4,479,911, Application EP 301,969 and Application EP 145,240; this method comprises the separate formation PA1 exhibit a controllable diameter, preferably of between 20 and 600 nm, PA1 are stable, PA1 can enclose water-soluble active substances, PA1 allow the preparation of both immediate-release or delayed-release forms, depending on the melting point of the gelified substance, PA1 can be used as the basis for the attachment of ligands, of substances which are poorly recognized by the reticuloendothelial system (stealthy microspheres) or of electrically-charged compounds (electrical targeting in electrotherapy), and PA1 are capable of being rendered stealthy (non-recognition by the reticuloendothelial system) when they exhibit a diameter of the order of 20-40 nm. PA1 as small unilamellar lipogelosomes (SULGS) and as large unilamellar lipogelosomes (LULGS) and PA1 as multilamellar lipogelosomes (MLGS). PA1 a) surface delipidation of unilamellar or multilamellar lipogelosomes by: PA1 unilamellar LGSs, when the non-delipidated starting LGSs, which were used for their preparation, were bilamellar, or PA1 multilamellar LGSs, when the non-delipidated starting LGSs, which were used for their preparation, were multilamellar; PA1 b) complete delipidation of unilamellar or multilamellar liposomes by: PA1 (a) the preparation of liposomes, called lipogelosomes, of the type containing n+1 lipid bilayers, including an outer lipid bilayer, and at least one inner polar aqueous phase containing a gelified substance, and PA1 (b) the delipidation of the said lipogelosomes. PA1 (1) the extraction of the surface lipid bilayer of the said unilamellar or multilamellar lipogelosomes by a water-immiscible organic solvent or a mixture of water-immiscible organic solvents; PA1 (2) the two-phase partition of the organic phase and of the aqueous phase; and PA1 (3) the separation of the aqueous phase containing the surface-delipidated gelified microspheres, as defined above. PA1 (1) the lipid extraction of unilamellar or multilamellar lipogelosomes by a water-miscible or partially water-miscible organic solvent or a mixture of water-miscible or partially water-miscible organic solvents; PA1 (2) the two-phase partition of the organic phase and of the aqueous phase; PA1 (3) the removal of the organic solvent from the aqueous phase; and PA1 (4) the separation of the gelified and completely delipidated microspheres, as defined above.
Within the meaning of the present invention, the term microcapsule or microsphere comprises only microcapsules or microspheres of matrix type.
Many substances can be encapsulated: it can relate to chemicals, such as medicaments, or alternatively to macromolecules, such as enzymes, and also to living cells.
Microspheres are used in many fields, such as pharmaceuticals, the biotechnology industry, cosmetology, the agri-foodstuffs industry, the paper-manufacturing industry, and the like.
A number of methods for the preparation of microcapsules have been described; mention may in particular be made of:
However, the microcapsules prepared by this method and by other analogous methods have the disadvantage of forming clusters (inter-adhesion of particles) during the preparation of the said microcapsules.
of an organic phase by dissolution of a suitable polymer in a volatile water-immiscible solvent and PA2 of an aqueous phase containing the advantageous active principle, PA2 (1) extraction of the surface lipid bilayer of the said unilamellar or multilamellar lipogelosomes by a water-immiscible organic solvent or a mixture of water-immiscible organic solvents; PA2 (2) two-phase partition of the organic phase and of the aqueous phase; and PA2 (3) separation of the aqueous phase containing the surface-delipidated gelified microspheres (removal of the outermost bilayer). PA2 these microspheres are surrounded by a polymerized or non-polymerized aqueous surface layer (Table I and FIGS. 2 and 3). PA2 (1) lipid extraction of unilamellar or multilamellar lipogelosomes by a water-miscible or partially water-miscible organic solvent or a mixture of water-miscible or partially water-miscible organic solvents; PA2 (2) two-phase partition of the organic phase and of the aqueous phase; PA2 (3) separation of the organic solvent or solvents from the aqueous phase; and PA2 (4) separation of the gelified and completely delipidated microspheres.
the addition of the aqueous phase to the organic phase, the mixing of the two phases with agitation and/or in the presence of an emulsifying agent and then the evaporation of the solvent, generally with agitation and at room temperature, in order to obtain the desired microcapsules.
Application EP 145,240 more particularly describes microcapsules produced by preparing a W/O emulsion (primary emulsion) comprising an inner aqueous layer containing a hydrophilic substance and a so-called medicament-retention substance (natural or synthetic mucilage or high-moleculer-weight compounds and more particularly gelatin) and an oily layer containing a polymer, preferably a polylactic acid or a copolymer of lactic acid and of glycolic acid or their mixtures, in a water-immiscible solvent such as dichloromethane, by then thickening or solidifying the said inner aqueous layer so as to obtain a viscosity greater than 5,000 centipoises, by then preparing a secondary W/O/W emulsion in the presence of a suitable surface-active agent and, finally, by subjecting the emulsion thus obtained to evaporation of the solvent. The process described in this Application makes it possible to obtain microcapsules with a diameter of between 0.5 and 400 .mu.m.
However, these microcapsules or microspheres of the prior art have the major disadvantage of having diameters of the order of a .mu.m or more (1-1250 .mu.m); now, there exist many applications for which it is necessary and/or particularly advantageous to be able to have available particles having a significantly smaller diameter, in particular of the order of an nm or more, for example between 20 and 600 nm.